chrX-50092130-C-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_001127898.4(CLCN5):c.2362C>T(p.Arg788*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
CLCN5
NM_001127898.4 stop_gained, splice_region
NM_001127898.4 stop_gained, splice_region
Scores
2
2
1
Splicing: ADA: 0.05692
2
Clinical Significance
Conservation
PhyloP100: 1.29
Genes affected
CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0363 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-50092130-C-T is Pathogenic according to our data. Variant chrX-50092130-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 208000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-50092130-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1079529Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 347577
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1079529
Hom.:
Cov.:
27
AF XY:
AC XY:
0
AN XY:
347577
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dent disease type 1 Pathogenic:1Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Apr 17, 2018 | This individual is hemizygous for a known nonsense variant, c.2362C>T, in the CLCN5 gene. This variant creates a premature stop codon (p.Arg788*). c.2362C>T (p.Arg788*) has not been listed in any population databases (i.e. ExAC, ESP or dbSNP). The variant has been reported in five unrelated patients with Dent's disease (Carballo-Trujillo et.al. Nephrol Dial Transplant 2003; 18(4): 717-723, Hoopes et.al. Kidney Int 2004; 65: 1615-1620, Wu et.al. Nephron Physiol 2009; 112: 53-62 & Grand et.al. Kidney Int 2009; 76: 999-1005). Segregation studies were performed by Carballo-Trujillo et.al and c.2362C>T was shown to cosegregate with the disease. In these reports, the variant is described as p.Arg718* (relative to transcript NM_000084.4). Functional studies in Xenopus laevis oocytes showed that this nonsense variant produced a truncated protein product and was lower in abundance in comparison to the wild-type. The truncation affected the cellular localisation of the protein (Grand et.al. Kidney Int 2009; 76: 999-1005). This variant is considered to be pathogenic according to the ACMG guidelines. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 29, 2024 | This sequence change creates a premature translational stop signal (p.Arg718*) in the CLCN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the CLCN5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dent disease (PMID: 12637640, 31672324). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208000). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLCN5 function (PMID: 19657328). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at